Small extracellular vesicles in combination with sleep-related circRNA3503:A targeted therapeutic agent with injectable thermosensitive hydrogel to prevent osteoarthritis

Osteoarthritis(OA),characterized by chondrocyte apoptosis and disturbance of the balance between catabolism and anabolism of the extracellular matrix(ECM),is the most common age-related degenerative joint disease worldwide.As sleep has been found to be beneficial for cartilage repair,and circular RNAs(circRNAs)have been demonstrated to be involved in the pathogenesis of OA,we performed RNA sequencing(RNA-seq),and found circRNA3503 was significantly increased after melatonin(MT)-induced cell sleep.Upregulation of circRNA3503 expression completely rescued the effects of interleukin-1β(IL-1β),which was used to simulate OA,on apoptosis,ECM degradation-and synthesis-related genes.Mechanistically,circRNA3503 acted as a sponge of hsa-miR-181c-3p and hsa-let-7b-3p.Moreover,as we previously showed that small extracellular vesicles(sEVs)derived from synovium mesenchymal stem cells(SMSCs)can not only successfully deliver nucleic acids to chondrocytes,but also effectively promote chondrocyte proliferation and migration,we assessed the feasibility of sEVs in combination with sleep-related circRNA3503 as an OA therapy.We successfully produced and isolated circRNA3503-loaded sEVs(circRNA3503-OE-sEVs)from SMSCs.Then,poly(D,L-lactide)-b-poly(ethylene glycol)-b-poly(D,L-lactide)(PDLLA-PEG-PDLLA,PLEL)triblock copolymer gels were used as carriers of sEVs.Through in vivo and in vitro experiments,PLEL@circRNA3503-OE-sEVs were shown to be a highly-effective therapeutic strategy to prevent OA progression.Through multiple pathways,circRNA3503-OE-sEVs alleviated inflammation-induced apoptosis and the imbalance between ECM synthesis and ECM degradation by acting as a sponge of hsa-miR-181c-3p and hsa-let-7b-3p.In addition,circRNA3503-OE-sEVs promoted chondrocyte renewal to alleviate the progressive loss of chondrocytes.Our results highlight the potential of PLEL@circRNA3503-OE-sEVs for preventing OA progression.

Double-network hydrogel enhanced by SS31-loaded mesoporous polydopamine nanoparticles:Symphonic collaboration of near-infrared photothermal antibacterial effect and mitochondrial maintenance for full-thickness wound healing in diabetes mellitus

Diabetic wound healing has become a serious healthcare challenge.The high-glucose environment leads to persistent bacterial infection and mitochondrial dysfunction,resulting in chronic inflammation,abnormal vascular function,and tissue necrosis.To solve these issues,we developed a double-network hydrogel,constructed with pluronic F127 diacrylate(F127DA)and hyaluronic acid methacrylate(HAMA),and enhanced by SS31-loaded mesoporous polydopamine nanoparticles(MPDA NPs).As components,SS31,a mitochondria-targeted peptide,maintains mitochondrial function,reduces mitochondrial reactive oxygen species(ROS)and thus regulates macrophage polarization,as well as promoting cell proliferation and migration,while MPDA NPs not only scavenge ROS and exert an anti-bacterial effect by photothermal treatment under near-infrared light irradiation,but also control release of SS31 in response to ROS.This F127DA/HAMA-MPDA@SS31(FH-M@S)hydrogel has characteristics of adhesion,superior biocompatibility and mechanical properties which can adapt to irregular wounds at different body sites and provide sustained release of MPDA@SS31(M@S)NPs.In addition,in a diabetic rat full thickness skin defect model,the FH-M@S hydrogel promoted macrophage M2 polarization,collagen deposition,neovascularization and wound healing.Therefore,the FH-M@S hydrogel exhibits promising therapeutic potential for skin regeneration.